Recent reports have demonstrated that fibrocystin/polyductin (FPC), whose mutations cause autosomal recessive polycystic kidney disease (ARPKD), can be cleaved and its extracellular domain (FPCEXD) is released through the apical surface of renal epithelial cells into the lumen of renal tubules (Hogan et al., 2009; Kaimori et al., 2007). We therefore hypothesize that FPCEXD may also play essential functions in tubulomorphogenesis and/or organogenesis. Lack of FPCEXD may result in cystogenesis of ARPKD. We have currently produced the mouse models expressing mutant Pkhd1 (Kim et al., 2008) and its transgene (Huang S, 2007), and developed renal collecting cell lines from these models as well (Hu et al., 2011). Besides the above model systems, we have also generated a new Pkhd1f65 mutant mouse line in which the entire single transmembrane domain of FPC (FPC-STD) can be spatially and temporally floxed out by induction of Cre recombinase. Using these model systems, we are able to determine whether the FPCEXD plays important functions in mouse embryogenesis or organogenesis, and whether FPCEXD overexpression in the developing mouse induces lethal phenotypes and cystic phenotypes; whether ectopic FPCEXD overexpression can rescue ARPKD phenotypes in our Pkhd1-deficient mice; and whether temporal restoration of FPCEXD function can halt or reverse cystic phenotypes in diseased kidneys, thus preserving or restoring normal renal tissue. By studying these mice as well as the cell lines derived from them, we will gain further insights into the role of secretory FPC in the regulation of embryogenesis, organogenesis, and cystogenesis. These findings will shed light on the pathogenesis of ARPKD and may develop fundamental basis for therapeutic intervention of human ARPKD. PUBLIC HEALTH RELEVANCE: This proposal will use our panel of novel Pkhd1 mouse models, which have been/are being produced, to unravel the domain functions of Fibrocystin.